title: LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas.
abstract: We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF-related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6-driven lymphomas may contribute to lymphomagenesis.
authors.affiliation: Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertolo
authors.forename: Sergio
authors.initials: S
authors.lastname: Roa
authors.forename: Ainara
authors.initials: A
authors.lastname: Sagardoy
authors.forename: Maria
authors.initials: M
authors.lastname: Mena-Varas
authors.forename: Eloy F
authors.initials: EF
authors.lastname: Robles
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martinez-Ferrandis
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.forename: Alberto
authors.initials: A
authors.lastname: Orta
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Salomon
authors.initials: S
authors.lastname: Amar
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.forename: Javier
authors.initials: J
authors.lastname: Briones
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Raquel
authors.initials: R
authors.lastname: Malumbres
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
mesh_terms: D001343:Autophagy / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007438:Introns; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C118738:LITAF protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha
keywords: B cells; Non-hodgkin lymphoma; autophagy; germinal centre; transcription factors